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Overexpression of hepatitis C virus NS5A protein induces chromosome instability via mitotic cell cycle dysregulation

机译:丙型肝炎病毒NS5A蛋白的过表达通过有丝分裂细胞周期失调诱导染色体不稳定

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Hepatocellular carcinoma (HCC) is a common primary cancer associated with high incidences of genetic variations including chromosome instability. Moreover, it has been demonstrated that hepatitis C virus (HCV) is one of the major causes of HCC. However, no previous work has assessed whether HCV proteins are associated with the induction of chromosome instability. Here, we found that liver cell lines constitutively expressing full-length or truncated versions of the HCV genome show a high incidence of chromosome instability. In particular, the overexpression of HCV NS5A protein in cultured liver cells was found to promote chromosome instability and aneuploidy. Further experiments showed that NS5A-induced chromosome instability is associated with aberrant mitotic regulations, such as, an unscheduled delay in mitotic exit and other mitotic impairments (e.g. multi-polar spindles). Thus, our results indicate that HCV NS5A protein may be directly involved in the induction of chromosome instability via mitotic cell cycle dysregulation, and provide novel insights into the molecular mechanisms of HCV-associated hepatocarcinogenesis. (c) 2006 Elsevier Ltd. All rights reserved.
机译:肝细胞癌(HCC)是常见的原发癌,与包括染色体不稳定在内的遗传变异高发生率有关。而且,已经证明丙型肝炎病毒(HCV)是HCC的主要原因之一。但是,以前没有工作评估HCV蛋白是否与染色体不稳定性有关。在这里,我们发现组成性表达HCV基因组的全长或截短版本的肝细胞系显示染色体不稳定的高发生率。特别地,发现在培养的肝细胞中HCV NS5A蛋白的过表达促进染色体不稳定和非整倍性。进一步的实验表明,NS5A诱导的染色体不稳定性与异常的有丝分裂调控有关,例如,有丝分裂退出的计划外延迟和其他有丝分裂障碍(例如多极纺锤体)。因此,我们的结果表明,HCV NS5A蛋白可能直接参与有丝分裂细胞周期失调引起的染色体不稳定,并为HCV相关肝癌的分子机制提供了新的见解。 (c)2006 Elsevier Ltd.保留所有权利。

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